Enantiospecific Synthesis of 9,10-Dihalocamphors

Abstract

A new, general and straightforward method for the enantiospecific synthesis of 9,10-dihalocamphors (including mixed derivatives) is reported and exemplified for the preparation of (+)-9,10-dibromocamphor (a well-known chiral intermediate) as well as (+)-9-bromo-10-chlorocamphor and (+)-9-bromo-10-iodocamphor (novel mixed dihalides). Our approach is based on a key stereocontrolled tandem electrophilic addition - Wagner-Meerwein rearrangement of optically pure 3-endo-(halomethyl)-3-methyl-2-methylenenorbornan-1-ols, which are easily obtained from readily accessible 9-halocamphors.

halides - ketones - electrophilic additions - chirality - bicyclic compounds

References

1a Ho T.-L. Enantioselective Synthesis: Natural Products from Chiral Terpenes   John Wiley and Sons; New York: 1992. 

1b Seyden-Penne J. Chiral Auxiliaries and Ligands in Asymmetric Synthesis   John Wiley and Sons; New York: 1995. 

1c Koskinen A. Asymmetric Synthesis of Natural Products   John Wiley and Sons; Chichester: 1998. 

1d Oppolzer W. Tetrahedron  1987,  43:  1969 

1e Blaser H.-U. Chem. Rev.  1992,  92:  935 

2 An interesting review on the preparation of camphor derivatives is: Money T. Nat. Prod. Rep.  1985,  253 

A plethora of examples on the synthetic use of chiral agents 2 and 3 has been reported (some of them are described in ref. ¹). About intermediate 1(H/CH = CH ₂ ) see:

3a Paquette LA. Zhao M. J. Am. Chem. Soc.  1998,  120:  5203 

3b Paquette LA. Wang H.-L. Su Z. Zhao M. J. Am. Chem. Soc.  1998,  120:  5213 

3c About catalyst 4 and other related derivatives see: García Martínez A. Teso Vilar E. García Fraile A. de la Moya Cerero S. Lora Maroto B. Tetrahedron: Asymmetry  2003,  14:  1959 ; and references therein

4a Stevens RV. Chang JH. Lapalme R. Schow S. Schlageter MG. Shapiro R. Weller HN. J. Am. Chem. Soc.  1983,  105:  7719 

4b Stevens RV. Lawrence DS. Tetrahedron  1985,  41:  93 

4c Stevens RV. Beaulieu N. Chang W.-H. Daniewski AR. Takeda T. Waldner A. Williard PG. Zutter U. J. Am. Chem. Soc.  1986,  108:  1039 

5a Richou O. Vaillancourt V. Faulkner DJ. Albizati KF. J. Am. Chem. Soc.  1989,  54:  4729 

5b Vaillancourt V. Albizati KF. J. Org. Chem.  1992,  57:  3627 

5c Agharahimi RM. LeBel NA. J. Org. Chem.  1995,  60:  1856 

6a Eck CR. Mills RW. Money T. J. Chem. Soc., Perkin Trans. 1  1975,  251 

6b Dadson WM. Lam M. Money T. Piper SE. Can. J. Chem.  1983,  61:  343 

7a Komarov IV. Gorichko MV. Kornilov MY. Tetrahedron: Asymmetry  1997,  8:  435 

7b Komarov IV. Monsees A. Kadyrov R. Fischer C. Schmidt U. Börner A. Tetrahedron: Asymmetry  2002,  13:  1615 

7c Komarov IV. Monsees A. Spannenberg A. Baumann W. Schmidt U. Fischer C. Börner A. Eur. J. Org. Chem.  2003,  138 

8 For a review see: de la Moya Cerero S. García Martínez A. Teso Vilar E. García Fraile A. Lora Maroto B. J. Org. Chem.  2003,  68:  1451 

9

Treatment of commercial enantiopure 3-endo-,9-dibromocamphor with Zn-HOAc (standard conditions, see ref. [2] ) produces the selective removal of the C(3)-bromine, giving place to pure 1(Br/H) in 95% yield.

10

The reaction of 1(Br/H) with Tf₂O was realized under the standard conditions described by us for other related 2-norbornanones (ref. [8] ). After chromatography (silica gel and hexane), pure triflate 5(Br) was obtained as a colorless liquid in 77% yield. [α]_D ²⁰ -55.5 (c 1.96, CH₂Cl₂). ¹H NMR and ¹³C NMR, IR and MS agree with the structure.

11

Alcohol 6(Br) was obtained by standard treatment of 5(Br) with LAH (e.g. ref. [8] ). Purification by chromatography (silica gel and CH₂Cl₂/Et₂O 95:5) yields pure alcohol 6(Br) as a colorless solid in 78% yield. Mp 72-74 °C. [α]_D ²⁰ -57.3 (c 0.67, CH₂Cl₂). ¹H NMR and ¹³C NMR, IR and MS agree with the structure.

12

A solution of 6(Br) and an excess of corresponding N-halosuccinimide (NYS) in CH₂Cl₂ was stirred at r.t. overnight. After standard work up and purification by chromatography (silica gel and hexane/CH₂Cl₂ 6: 4), corresponding pure 1(Br/Y) was obtained as a colorless solid. Compound 1(Br/Br): 85% yield. Characterization data agree with the previously described in ref. [6b] Compound 1(Br/Cl): 83 yield. Mp 64-66 °C. [α]_D ²⁰ +88.6 (c 0.98, CH₂Cl₂). ¹H NMR (200 MHz, CDCl₃): δ = 3.86 (d, J = 12.7 Hz, 1 H), 3.71 (d, J = 10.7 Hz, 1 H), 3.66 (d, J = 12.7 Hz, 1 H), 3.56 (d, J = 10.7 Hz, 1 H), 2.59 (dd, J = 4.5 Hz, J = 4.5 Hz, 1 H), 2.48-2.25 (m, 2 H), 2.14-1.93 (m, 1 H), 1.98 (d, J = 18.5 Hz, 1 H), 1.61-1.38 (m, 2 H), 1.12 (s, 3 H) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 214.2, 62.7, 52.2, 42.3, 41.2, 41.1, 39.9, 25.8, 24.8, 16.9 ppm. IR (CCl₄): ν = 2964, 1747, 1415, 1385 cm^-1. MS: m/z (%) = 185 (3) [M⁺ - 79], 171 (31), 121 (24), 107 (100), 93 (31), 79 (42), 39 (50). HRMS: calcd for C₁₀H₁₄BrClO: 263.9916. Found: 263.9915. Compound 1(Br/I): 80% yield. Mp 120-122 °C. [α]_D ²⁰ +44.9 (c 0.72, CH₂Cl₂). ¹H NMR (200 MHz, CDCl₃): δ = 3.67 (dd, J = 10.5 Hz, J = 1.0 Hz, 1 H), 3.55 (d, J = 10.5 Hz, 1 H), 3.44 (d, J = 11.2 Hz, 1 H), 3.17 (d, J = 11.2 Hz, 1 H), 2.61 (dd, J = 4.4 Hz, J = 4.4 Hz, 1 H), 2.40 (dm, J = 18.5 Hz, 1 H), 2.23-1.91 (m, 2 H), 1.98 (d, J = 18.5 Hz, 1 H), 1.70-1.43 (m, 2 H), 1.07 (s, 3 H) ppm. ¹³C NMR (50 MHz, CDCl₃):
δ = 214.0, 60.8, 52.4, 42.0, 41.5, 39.4, 29.5, 26.1, 16.8, 0.3 ppm. IR (CCl₄): ν = 2962, 1745, 1456, 1058 cm^-1. MS: m/z (%) = 231 (10) [M⁺·- 127], 229 (9), 189 (4), 187 (4), 149 (6), 121 (70), 107 (100), 93 (45), 79 (60), 67 (22), 41 (58). HRMS: calcd for C₁₀H₁₄BrIO: 355.9273. Found: 355.9269.